Percutaneous transvascular coronary angioplasty and stenting is one of the most commonly employed interventional procedures for the treatment of coronary artery disease. A frequent long-term complication of this treatment modality is the phenomenon of in stent restenosis (ISR) which occurs at the site of the atherosclerotic lesion, leading to the obstruction of dilated arteries in 20-30% of patients within 6 months of stenting. The primary contributors of this multifactorial pathological event are incomplete endothelial recovery and vascular SMC proliferation in the inner lining of the artery. Several approaches have been used to improve stent design and durability, such as the use of covered stents to improve biocompatibility of the stent material and intracoronary radiation to inhibit inflammation and proliferation of smooth muscle cells. Radiation therapy, although effective, was accompanied by delayed healing and incomplete endothelial recovery; whereas coated stents have not been completely successful in eliminating the problem.
The introduction of drug eluting stent (DES) has been seen as a significant improvement in the existing stent design. The drugs used are mostly antiproliferative which target the smooth muscle cell proliferation and related inflammatory systems. But the direct use of these chemical factors is limited by the problems associated with drug washout, their inadvertent effects on non-target cells, as well as the unselected inhibition of vascular cell division by the drugs leading to incomplete endothelial recovery of stented vessels. Moreover, recent long term meta-analysis of DES studies demonstrating increased risk of late-stent thrombosis has raised questions on the long term safety of DES. As the pathological recurrence of stenosis mainly stem from the endothelial cell lining damage and dysfunction caused by the stent implantation, approaches to promote accelerated re-endothelialization can be of significant importance to reduce the risk of ISR and late in-stent thrombosis. Moreover, this strategy will evade the harmful consequences of discontinuation of antiplatelet drug therapy which are otherwise needed post DES implantation. Therapeutic induction of vascular cells by transferring proangiogenic vascular genes, such as Vegf, to promote re-endothelization has been proposed as a potent way to attenuate neointima formation and reduce restenosis. Vegf cytokines are a family of endothelial specific mitogenic factors that bind to tyrosine kinase receptors 1 and 2, expressed almost exclusively on the endothelial cells, and widely used for selective proliferation and repair of damaged vascular endothelial structures. Although mammalian viral vectors have been efficiently used for vascular gene therapy, clinical applications are limited due to safety concerns related to risk of inclusion of replication competent viruses and proper optimization of the human tolerization level to these pathogens. Moreover, there are associated problems of immunogenicity due to high viral titer, induction of innate toxicity and inflammatory reactions coupled with the inherent risk of viral integration to the host genome. On the other hand, non-viral gene delivery systems are mainly limited by low in vivo gene transfer efficiencies.
Wound healing is a complex physiological event which leads to the replacement of the injury tissue by a new one. The adequate healing of a wound requires the proliferation and/or dedifferentiation of cells in the vicinity of the wound as well as the production and/or remodeling of the extracellular matrix, but also a return to quiescence once the scar has been formed (differentiation of cells, halt in proliferation and in matrix remodeling). In some pathological instances, the healing process fails or delays the return to quiescence and as such promotes the hyperplasia of cells, the production of an abnormal amount of extracellular matrix (e.g. too much or too little) and can even lead to the formation of a pathological scar (e.g. hypotrophic/hypertrophic scar in the skin, restenosis in large vessels for example).
In situations where the wound healing process is susceptible to induce pathological side-effects (in stent restenosis for example), it is would be desirable to be provided with a gene-delivery system which could favor the homeostatic wound healing process by providing, locally, in the vicinity of a wound, a therapeutic nucleic acid molecule for transduction by the cells of the host. Since the process of wound healing is performed within a specific time window, in some embodiments, it would be highly desirable to be provided with a gene-delivery system which allows a transient transduction of the therapeutic nucleic acid molecule during to the wound healing process. In addition, since a wound is usually limited to a specific location within the host, in some embodiment, it would be highly desirable to be provided with a gene-delivery system which specifically allows the transduction of the therapeutic nucleic acid to the vicinity of the wound. Preferably, the gene-delivery system limits (and in some embodiments) prevents the immune reaction associated with the transduction of the therapeutic nucleic acid molecule.